Inhibitors of the HIV viral protease have been developed relatively recently and their use began only in 1996. Currently, they are considered the most effective drugs against HIV infection. Unfortunately, most current proteases inhibitors are relatively large hydrophobic molecules that possess rather low bioavailability. A high pill burden is therefore required to attain the therapeutic dose in a patient. This is a deterrent, which too often results in patient non-compliance and inadequate treatment results. This situation leads to sub-optimal therapeutic drug concentration that in turns leads to the development of HIV resistant strains. Consequently, there is an urgent need to improve the solubility and bioavailability of proteases inhibitors.
Protease inhibitors have also been developed in the form of prodrugs such as those described, for example, in U.S. Pat. No. 6,436,989 to Hale et al, the entire content of which is incorporated herein by reference. These prodrugs possess favourable aqueous solubility, high oral bioavailability and allow the in vivo generation of the active ingredient. However, it is well known that HIV has the ability to develop resistance to the currently available drugs. A need remains for alternative HIV protease inhibitors active towards wild-type and resistant viral strains and which shows enhanced solubility and bioavailability.
The synthesis of a unique class of aromatic derivatives which are inhibitors of aspartyl proteases is described in U.S. Pat. No. 6,632,816 to Stranix et al, the entire content of which is incorporated herein by reference. This patent includes, more particularly, N,-synthetic amino acid substituted L-lysine derivatives possessing potent aspartyl protease inhibitory properties. Lysine based compounds demonstrating enhanced aqueous solubility and bioavailability as well as their method of preparation have also been described in U.S. application Ser. No. 09/902,935 (Stranix et al.,) published Feb. 2, 2006 under publication No. US2006/0025592A1.
Efficient and improved route of synthesizing these compounds are needed in order to develop commercially-viable processes. A desirable route of synthesis should produce the compounds in a good yield, with the minimum number of step possible and in a manner that is of minimum impact to the environment in terms of disposing of waste-materials. Intermediate compounds are also of help in facilitating the synthesis of end compounds. There thus remains a need for optimizing synthesis of lysine based compounds.
The present invention seeks to meet these and other needs.